Objective To investigate endoscopic retrograde cholangiopancreatography (ERCP) in the treatment of large common bile duct stone with endoscopic papillary balloon dilatation (EPBD) first or mechanical lithotripsy first. EPBD first or lithotripsy first were compared for stone removal efficiency and post-ERCP complications. Methods A prospective study of 40 patients with choledocholithiasis from January 2021 to January 2022 was done. Patients were divided into lithotripsy first group and EPBD first group each 20 cases using random number table. Stone remove time, stone removal efficiency (cm³/min), the rate of residual stones and rate of post-ERCP pancreatitis were compared between two groups. Results All cases underwent stone removal one time successfully. There was no statistically significant difference in maximum diameter of stone, single or multiple stone, stone volumes (cm³), time for stone remove and operative time between two groups. The stone removal efficiency (cm³/min) in lithotripsy first group was significantly higher than that in EPBD first group, (0.91±0.58) cm³/min vs. (0.51±0.17) cm³/min, P=0.048. While the procedure numbers of stone tool passing papilla in lithotripsy first group were less than those in EPBD first group, (4.9±1.7) vs. (7.9±2.2), P=0.021. The differences in the rate of residual stone and the rate of post-ERCP complications were not significant statistically. Post-ERCP serum amylase level [(196±158) U/L vs. (332±265) U/L, P=0.02] and the cases with hyperamylasemia (2 cases vs. 8 cases, P=0.028) in lithotripsy first group were significantly lower than those in EPBD first group. No case with severe pancreatitis,gastrointestinal bleeding or duodenal perforation occurred in either group. Conclusions Using lithotripsy before EPBD procedure in treatment of difficult common bile duct stone could increase stone removal efficiency and reduce both procedure number of stone tool passing papilla and rate of post-ERCP hyperamylasemia.